Background In primary cardiovascular disease prevention, early identification of high-risk individuals is crucial. Genetic information allows for the stratification of genetic predispositions and lifetime risk of cardiovascular disease. However, towards clinical application, the added value over clinical predictors later in life is crucial. Currently, this genotype-phenotype relationship and implications for overall cardiovascular risk are unclear. MethodsIn this study, we developed and validated a neural network-based risk model (NeuralCVD) integrating polygenic and clinical predictors in 395 713 cardiovascular disease-free participants from the UK Biobank cohort. The primary outcome was the first record of a major adverse cardiac event (MACE) within 10 years. We compared the NeuralCVD model with both established clinical scores (SCORE, ASCVD, and QRISK3 recalibrated to the UK Biobank cohort) and a linear Cox-Model, assessing risk discrimination, net reclassification, and calibration over 22 spatially distinct recruitment centres. Findings The NeuralCVD score was well calibrated and improved on the best clinical baseline, QRISK3 (∆Concordance index [C-index] 0•01, 95% CI 0•009-0•011; net reclassification improvement (NRI) 0•0488, 95% CI 0•0442-0•0534) and a Cox model (∆C-index 0•003, 95% CI 0•002-0•004; NRI 0•0469, 95% CI 0•0429-0•0511) in risk discrimination and net reclassification. After adding polygenic scores we found further improvements on population level (∆C-index 0•006, 95% CI 0•005-0•007; NRI 0•0116, 95% CI 0•0066-0•0159). Additionally, we identified an interaction of genetic information with the pre-existing clinical phenotype, not captured by conventional models. Additional high polygenic risk increased overall risk most in individuals with low to intermediate clinical risk, and age younger than 50 years. Interpretation Our results demonstrated that the NeuralCVD score can estimate cardiovascular risk trajectories for primary prevention. NeuralCVD learns the transition of predictive information from genotype to phenotype and identifies individuals with high genetic predisposition before developing a severe clinical phenotype. This finding could improve the reprioritisation of otherwise low-risk individuals with a high genetic cardiovascular predisposition for preventive interventions.

De novo protein design enhances our understanding of the principles that govern protein folding and interactions, and has the potential to revolutionize biotechnology through the engineering of novel protein functionalities. Despite recent progress in computational design strategies, de novo design of protein structures remains challenging, given the vast size of the sequence-structure space. AlphaFold2 (AF2), a state-of-the-art neural network architecture, achieved remarkable accuracy in predicting protein structures from amino acid sequences. This raises the question whether AF2 has learned the principles of protein folding sufficiently for de novo design. Here, we sought to answer this question by inverting the AF2 network, using the prediction weight set and a loss function to bias the generated sequences to adopt a target fold. Initial design trials resulted in de novo designs with an overrepresentation of hydrophobic residues on the protein surface compared to their natural protein family, requiring additional surface optimization. In silico validation of the designs showed protein structures with the correct fold, a hydrophilic surface and a densely packed hydrophobic core. In vitro validation showed that several designs were folded and stable in solution with high melting temperatures. In summary, our design workflow solely based on AF2 does not seem to fully capture basic principles of de novo protein design, as observed in the protein surface's hydrophobic vs. hydrophilic patterning. However, with minimal post-design intervention, these pipelines generated viable sequences as assessed experimental characterization. Thus such pipelines show the potential to contribute to solving outstanding challenges in de novo protein design.

De novo protein design enhances our understanding of the principles that govern protein folding and interactions, and has the potential to revolutionize biotechnology through the engineering of novel protein functionalities. Despite recent progress in computational design strategies, de novo design of protein structures remains challenging, given the vast size of the sequence-structure space. AlphaFold2 (AF2), a state-of-the-art neural network architecture, achieved remarkable accuracy in predicting protein structures from amino acid sequences. This raises the question whether AF2 has learned the principles of protein folding sufficiently for de novo design. Here, we sought to answer this question by inverting the AF2 network, using the prediction weight set and a loss function to bias the generated sequences to adopt a target fold. Initial design trials resulted in de novo designs with an overrepresentation of hydrophobic residues on the protein surface compared to their natural protein family, requiring additional surface optimization. In silico validation of the designs showed protein structures with the correct fold, a hydrophilic surface and a densely packed hydrophobic core. In vitro validation showed that 7 out of 39 designs were folded and stable in solution with high melting temperatures. In summary, our design workflow solely based on AF2 does not seem to fully capture basic principles of de novo protein design, as observed in the protein surface's hydrophobic vs. hydrophilic patterning. However, with minimal post-design intervention, these pipelines generated viable sequences as assessed experimental characterization. Thus, such pipelines show the potential to contribute to solving outstanding challenges in de novo protein design.

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